Rett syndrome is a devastating neurological disorder characterized by autism, language skill loss, stereotyped behaviors, motor delays, cognitive deficits, seizures, and breathing abnormalities. Most cases result from mutations in or loss of the protein MeCP2, a transcription factor that binds to methylated CpG regions of DNA. Knockout of MeCP2 in mice recapitulates many Rett phenotypes and re-expression of MeCP2 in adult mouse neurons corrects phenotypic deficits, suggesting that treatments given after disease development may be therapeutically viable. However, children with MeCP2 Duplication syndrome also exhibit significant Rett-like symptoms, indicating that a precise level of MeCP2 is critical for maintaining normal neuronal function. We have found that the gene encoding metabotropic glutamate receptor 7 (GRM7/mGlu7), a receptor which modulates glutamate and GABA release, is positively regulated by MeCP2 both in vitro and in an in vivo Mecp2 knockout mouse model. Importantly, we have found that mGlu7 mRNA and protein levels are significantly decreased in multiple brain areas in Mecp2 KO mice. These results suggest that the GRM7 gene appears to be true and novel target of MeCP2. If correct, we predict that mGlu7 levels will be elevated in mice overexpressing MeCP2, which represent a model for MeCP2 Duplication syndrome. As one function of mGlu7 activation is to decrease glutamate release from presynaptic terminals, we hypothesized that aberrantly decreased levels of mGlu7 in Mecp2 KO mice enhances glutamatergic tone. It has been demonstrated in Mecp2 KO, knock-in, and overexpressing mice that synaptic transmission, as well as long term potentiation, at Schaffer Collateral-CA1 (SC-CA1) synapses is altered. Interestingly, the impairment in each case appears to be mediated, in part, by a presynaptic mechanism, with mice lacking Mecp2 exhibiting reduced paired pulse facilitation, an observation consistent with increased glutamate release from presynaptic terminals. In contrast, mice overexpressing Mecp2 show increases in paired pulse ratios, suggestive of decreased glutamate release. As mGlu7 is the predominant mGlu present at the SC-CA1 synapse in adult animals, these defects in neurotransmission, coupled with our findings that mGlu7 levels are reduced in Mecp2 KO mice, are consistent with a role for presynaptic mGlu7 as a major controller of glutamate release at SC-CA1 synapses, potentially resulting in cognitive deficits seen in these animals. We have confirmed previous results showing that synaptic plasticity and long term potentiation are altered in Mecp2-/y mice and show, importantly, that potentiation of mGlu7 activity can rescue these defects. We propose to test the hypotheses that mGlu7 levels are conversely increased in an MeCP2 Duplication mouse model, further substantiating a role for MeCP2 in mGlu7 gene regulation. Additionally, we will test the hypotheses that modulation of mGlu7 activity using pharmacological tools will normalize synaptic plasticity and behavioral deficits in mice under- and overexpressing the MeCP2 protein.